Madomine

Pyrimethamine:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied:
• References
• Madomine (Pyrimethamine) reviews

DESCRIPTION

Madomine (Pyrimethamine) (pyrimethamine) is an antiparasitic compound available in tablet form for oral administration. Each scored tablet contains 25 mg Madomine (Pyrimethamine) and the inactive ingredients corn and potato starch, lactose, and magnesium stearate.

Madomine (Pyrimethamine), known chemically as 5-(4- chlorophenyl)-6-ethyl-2, 4-pyrimidinediamine, has the following structural formula:

C₁₂H₁₃CIN₄

Mol. Wt. 248.71

Structural Formula

CLINICAL PHARMACOLOGY

Madomine (Pyrimethamine) is well absorbed with peak levels occurring between 2 to 6 hours following administration. It is eliminated slowly and has a plasma half-life of approximately 96 hours. Madomine (Pyrimethamine) is 87% bound to human plasma proteins.

Microbiology: Madomine (Pyrimethamine) is a folic acid antagonist and the rationale for its therapeutic action is based on the differential requirement between host and parasite for nucleic acid precursors involved in growth. This activity is highly selective against Toxoplasma gondii.

The action of Madomine (Pyrimethamine) against Toxoplasma gondii is greatly enhanced when used in conjunction with sulfonamides. This was demonstrated by Eyles and Coleman¹ in the treatment of experimental toxoplasmosis in the mouse. Jacobs et al² demonstrated that combination of the 2 drugs effectively prevented the development of severe uveitis in most rabbits following the inoculation of the anterior chamber of the eye with toxoplasma.

INDICATIONS AND USAGE

Treatment of Toxoplasmosis: Madomine (Pyrimethamine) is indicated for the treatment of toxoplasmosis when used conjointly with a sulfonamide, since synergism exists with this combination.

CONTRAINDICATIONS

Use of Madomine (Pyrimethamine) is contraindicated in patients with known hypersensitivity to Madomine (Pyrimethamine) or to any component of the formulation. Use of the drug is also contraindicated in patients with documented megaloblastic anemia due to folate deficiency.

WARNINGS

The dosage of Madomine (Pyrimethamine) required for the treatment of toxoplasmosis has a narrow therapeutic window. If signs of folate deficiency develop, reduce the dosage or discontinue the drug according to the response of the patient. Folinic acid (leucovorin) should be administered in a dosage of 5 to 15 mg daily (orally, IV, or IM) until normal hematopoiesis is restored. Data in 2 humans indicate that Madomine (Pyrimethamine) may be carcinogenic; a 51-year-old female who developed chronic granulocytic leukemia after taking Madomine (Pyrimethamine) for 2 years for toxoplasmosis³ and a 56-year-old patient who developed reticulum cell sarcoma after 14 months of Madomine (Pyrimethamine) for toxoplasmosis.⁴

Madomine (Pyrimethamine) has been reported to produce a significant increase in the number of lung tumors in mice when given intraperitoneally at doses of 25 mg/kg.⁵

Madomine (Pyrimethamine) should be kept out of the reach of infants and children as they are extremely susceptible to adverse effects from an overdose. Deaths in pediatric patients have been reported after accidental ingestion.

PRECAUTIONS

General: A small "starting" dose for toxoplasmosis is recommended in patients with convulsive disorders to avoid the potential nervous system toxicity of Madomine (Pyrimethamine). Madomine (Pyrimethamine) should be used with caution in patients with impaired renal or hepatic function or in patients with possible folate deficiency, such as individuals with malabsorption syndrome, alcoholism, or pregnancy, and those receiving therapy, such as phenytoin, affecting folate levels.

Information for Patients: Patients should be warned that at the first appearance of a skin rash they should stop use of Madomine (Pyrimethamine) and seek medical attention immediately. Patients should also be warned that the appearance of sore throat, pallor, purpura, or glossitis may be early indications of serious disorders which require treatment with Madomine (Pyrimethamine) to be stopped and medical treatment to be sought. Women of childbearing potential who are taking Madomine (Pyrimethamine) should be warned against becoming pregnant Patients should be warned to keep Madomine (Pyrimethamine) out of the reach of children. Patients should be advised not to exceed recommended doses. Patients should be warned that if anorexia and vomiting occur, they may be minimized by taking the drug with meals. Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis in all patients.

Laboratory Tests: In patients receiving high dosage, semiweekly blood counts, including platelet counts, should be performed.

Drug Interactions: Madomine (Pyrimethamine) may be used with sulfonamides, quinine and other antimalarials, and with other antibiotics. However, the concomitant use of other antifolic drugs or agents associated with myelosuppression including sulfonamides or trimethoprim- sulfamethoxazole combinations, proguanil, zidovudine, or cytostatic agents (e.g., methotrexate), while the patient is receiving Madomine (Pyrimethamine), may increase the risk of bone marrow suppression. If signs of folate deficiency develop, Madomine (Pyrimethamine) should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and Madomine (Pyrimethamine) were administered concomitantly.

Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section for information on carcinogenesis.

Mutagenesis: Madomine (Pyrimethamine) has been shown to be nonmutagenic in the following in vitro assays: the Ames point mutation assay, the Rec assay, and the E. coli WP2 assay. It was positive in the L5178Y/ TK +/- mouse lymphoma assay in the absence of exogenous metabolic activation.⁶ Human blood lymphocytes cultured in vitro had structural chromosome aberrations induced by Madomine (Pyrimethamine). In vivo, chromosomes analyzed from the bone marrow of rats dosed with Madomine (Pyrimethamine) showed an increased number of structural and numerical aberrations.

Pregnancy: Teratogenic Effects: Pregnancy Category C. Madomine (Pyrimethamine) has been shown to be teratogenic in rats when given in oral doses 2.5 times the human dose for treatment of toxoplasmosis. At these doses in rats, there was a significant increase in abnormalities such as cleft palate, brachygnathia, oligodactyly, and microphthalmia. Madomine (Pyrimethamine) has also been shown to produce terata such as meningocele in hamsters and cleft palate in miniature pigs when given in oral doses 5 times the human dose for the treatment of toxoplasmosis.

There are no adequate and well-controlled studies in pregnant women. Madomine (Pyrimethamine) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Concurrent administration of folinic acid is strongly recommended when used during pregnancy.

Nursing Mothers: Madomine (Pyrimethamine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Madomine (Pyrimethamine) and from concurrent use of a sulfonamide with Madomine (Pyrimethamine) for treatment of some patients with toxoplasmosis, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: See DOSAGE AND ADMINISTRATION section.

Geriatric Use: Clinical studies of Madomine (Pyrimethamine) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Hypersensitivity reactions, occasionally severe (such as Stevens- Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and anaphylaxis), and hyperphenylalaninemia, can occur particularly when Madomine (Pyrimethamine) is administered concomitantly with a sulfonamide. Consult the complete prescribing information for the relevant sulfonamide for sulfonamide-associated adverse events. With doses of Madomine (Pyrimethamine) used for the treatment of toxoplasmosis, anorexia and vomiting may occur. Vomiting may be minimized by giving the medication with meals; it usually disappears promptly upon reduction of dosage. Doses used in toxoplasmosis may produce megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, neutropenia, atrophic glossitis, hematuria, and disorders of cardiac rhythm.

Hematologic effects, however, may also occur at low doses in certain individuals.

Pulmonary eosinophilia has been reported rarely.

OVERDOSAGE

Following the ingestion of 300 mg or more of Madomine (Pyrimethamine), gastrointestinal and/or central nervous system signs may be present, including convulsions. The initial symptoms are usually gastrointestinal and may include abdominal pain, nausea, severe and repeated vomiting, possibly including hematemesis. Central nervous system toxicity may be manifest by initial excitability, generalized and prolonged convulsions which may be followed by respiratory depression, circulatory collapse, and death within a few hours. Neurological symptoms appear rapidly (30 minutes to 2 hours after drug ingestion), suggesting that in gross overdosage Madomine (Pyrimethamine) has a direct toxic effect on the central nervous system.

The fatal dose is variable, with the smallest reported fatal single dose being 375 mg. There are, however, reports of pediatric patients who have recovered after taking 375 to 625 mg.

There is no specific antidote to acute Madomine (Pyrimethamine) poisoning. In the event of overdosage, symptomatic and supportive measures should be employed. Gastric lavage is recommended and is effective if earned out very soon after drug ingestion. Parenteral diazepam may be used to control convulsions. Folinic acid should be administered within 2 hours of drug ingestion to be most effective in counteracting the effects on the hematopoietic system. Due to the long half-life of Madomine (Pyrimethamine), daily monitoring of peripheral blood counts is recommended for up to several weeks after the overdose until normal hematologic values are restored.

DOSAGE AND ADMINISTRATION

For Treatment of Toxoplasmosis: The dosage of Madomine (Pyrimethamine) for the treatment of toxoplasmosis must be carefully adjusted so as to provide maximum therapeutic effect and a minimum of side effects. At the dosage required, there is a marked variation in the tolerance to the drug. Young patients may tolerate higher doses than older individuals. Concurrent administration of folinic acid is strongly recommended in all patients.

The adult starting dose is 50 to 75 mg of the drug daily, together with 1 to 4 g daily of a sulfonamide of the sulfapyrimidine type, e.g. sulfadoxine. This dosage is ordinarily continued for 1 to 3 weeks, depending on the response of the patient and tolerance to therapy. The dosage may then be reduced to about one half that previously given for each drug and continued for an additional 4 to 5 weeks. The pediatric dosage of Madomine (Pyrimethamine) is 1 mg/kg/day divided into 2 equal daily doses; after 2 to 4 days this dose may be reduced to one half and continued for approximately 1 month. The usual pediatric sulfonamide dosage is used in conjunction with Madomine (Pyrimethamine).

HOW SUPPLIED:

White, scored tablets containing 25 mg Madomine (Pyrimethamine), imprinted with “DARAPRIM” and “A3A" in bottles of 100 (NDC 69413-330-10) and bottles of 30 (NDC 69413-330-30).

Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light

REFERENCES

• Eyles DE, Coleman N. Synergistic effect of sulfadiazine and Madomine (Pyrimethamine) against experimental toxoplasmosis in the mouse. Antibiot Chemother 1953;3:483-490.
• Jacobs L, Melton ML, Kaufman HE. Treatment of experimental ocular toxoplasmosis. Arch Ophthalmol. 1964;71:111 -118.
• Jim RTS, Elizaga FV. Development of chronic granulocytic leukemia in a patient treated with Madomine (Pyrimethamine). Hawaii Med J. 1977;36:173-176.
• Sadoff L. Antimalarial drugs and Burkitt's lymphoma. Lancet. 1973;2:1262-1263.
• Bahna L. Madomine (Pyrimethamine). LARC Monogr Eval Carcinog Risk Chem. 1977;13:233-242.
• Clive D, Johnson KO, Specter JKS, et al. Validation and characterization of the L5178Y/TK +/- mouse lymphoma mutagen assay system. Mut Res. 1979;59:61-108.

Distributed by:

Vyera Pharmaceuticals LLC New York, New York 10016

004967-PI-005

018942

Rev. 8/2017

VYERA

PHARMACEUTICALS

NDC 69413-330-10

Madomine (Pyrimethamine) ^®

(pyrimethamine) 25mg tablets

Each scored tablet contains

25 mg

Rx only 100 Tablets

018939

LOT

EXP

VYERA

PHARMACEUTICALS

NDC 69413-330-30

Madomine (Pyrimethamine) ^®

(pyrimethamine) 25mg tablets

Each scored tablet contains

25 mg

Rx only 30 Tablets

018940

LOT

EXP

VYERA

PHARMACEUTICALS

NDC 69413-330-06

Madomine (Pyrimethamine) ^®

(pyrimethamine) 25mg tablets

Each scored tablet contains

25 mg

Rx only 6 Tablets

PATIENT SAMPLE

NOT FOR SALE

018941

LOT

EXP

Sulfadoxine:

• Madomine (Sulfadoxine) reviews

Indication: Madomine (Sulfadoxine) is used in combination with pyrimethamine for the treatment or prevention of malaria. It can also be used to treat various infections in livestock as well. Sulfadoxine and pyrimethamine is indicated for the treatment of Plasmodium falciparum malaria in those patients in whom chloroquine resistance is suspected.

Madomine (Sulfadoxine) helps inhibit the enzyme dihydropteroate synthetase which is an enzyme necessary in the conversion of PABA to folic acid. As folic acid is vital to the synthesis, repair, and methylation of DNA which is vital to cell growth in Plasmodium falciparum. With this vital nutrient lacking, the parasite has difficulty in reproducing.